Talo, M. | bioRxiv Science

bioRxiv2025

ProtFun: A Protein Function Prediction Model Using Graph Attention Networks with a Protein Large Language Model

Understanding protein functions facilitates the identification of the underlying causes of many diseases and guides the research for discovering new therapeutic targets and medications. With the advancement of high throughput technologies, obtaining novel protein sequences has been a routine process. However, determining protein functions experimentally is cost- and labor-prohibitive. Therefore, it is crucial to develop computational methods for automatic protein function prediction. In this study, we propose a multi-modal deep learning architecture called ProtFun to predict protein functions. ProtFun integrates protein large language model (LLM) embeddings as node features in a protein family network. Employing graph attention networks (GAT) on this protein family network, ProtFun learns protein embeddings, which are integrated with protein signature representations from InterPro to train a protein function prediction model. We evaluated our architecture using three benchmark datasets. Our results showed that our proposed approach outperformed current state-of-the-art methods for most cases. An ablation study also highlighted the importance of different components of ProtFun. The data and source code of ProtFun is available at https://github.com/bozdaglab/ProtFun under Creative Commons Attribution Non Commercial 4.0 International Public License.

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bioRxiv2025

Top-DTI: Integrating Topological Deep Learning and Large Language Models for Drug Target Interaction Prediction

MotivationThe accurate prediction of drug-target interactions (DTI) is a crucial step in drug discovery, providing a foundation for identifying novel therapeutics. Traditional drug development is both costly and time-consuming, often spanning over a decade. Computational approaches help narrow the pool of compound candidates, offering significant starting points for experimental validation. In this study, we propose Top-DTI framework for predicting DTI by integrating topological data analysis (TDA) with large language models (LLMs). Top-DTI leverages persistent homology to extract topological features from protein contact maps and drug molecular images. Simultaneously, protein and drug LLMs generate semantically rich embeddings that capture sequential and contextual information from protein sequences and drug SMILES strings. By combining these complementary features, Top-DTI enhances predictive performance and robustness. ResultsExperimental results on the public BioSNAP and Human DTI benchmark datasets demonstrate that the proposed Top-DTI model outperforms state-of-the-art approaches across multiple evaluation metrics, including AUROC, AUPRC, sensitivity, and specificity. Furthermore, the Top-DTI model achieves superior performance in the challenging cold-split scenario, where the test and validation sets contain drugs or targets absent from the training set. This setting simulates real-world scenarios and highlights the robustness of the model. Notably, incorporating topological features alongside LLM embeddings significantly improves predictive performance, underscoring the value of integrating structural and sequence-based representations. AvailabilityThe data and source code of Top-DTI is available at https://github.com/bozdaglab/Top_DTI under Creative Commons Attribution Non Commercial 4.0 International Public License.

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